Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumors of the gastrointestinal tract (about 1-3% of all gastrointestinal malignancies). Approximately 85% of the GISTs harbor activating (i.e. gain-of-function) mutations in cKIT gene encoding a stem cell factor receptor having tyrosine kinase activity. Furthermore, about 35% of the GISTs with a wild-type cKIT gene instead have mutations in another gene, PDGFRA (platelet derived growth factor receptor-alpha), which is a related tyrosine kinase (reviewed, e.g., in. Corless, C. L. and Heinrich, M. C. (2008) Annu. Rev. Pathol. 3, 557-586). These mutations are an early event in GIST progression.
The onco-proteins cKIT and PDGFRA serve as targets for the small molecule tyrosine kinase inhibitors such as imatinib and sunitinib. Notably, treatment with imatinib is not curative unless complete resection of the tumor is possible. In advanced, metastasized or irresectable GISTs, a partial remission can be attained in about 50% of the patients treated with imatinib. However, most patients still experience disease progression while receiving imatinib (see, e.g., Verweij, J. et al. (2004) Lancet 364, 1127-34; Blanke, C. D. et al. (2008) J. Clin. Oncol. 26, 626-632). In addition, such patients were also found to only transiently respond to sunitinib (Demetri, G. D. et al. (2006) Lancet 368, 1329-1338).
Even though imatinib and sunitinib exhibited remarkable clinical effects, their efficacies greatly depend on the genotype of the GIST. The drugs met intrinsic or acquired resistance during the treatment, of which the molecular mechanisms were mostly dependent on the genotype of GIST as well, including primary mutations or secondary mutations in the kinase domains of the corresponding target genes, respectively. Thus, advanced GISTs may require multidisciplinary treatment.
From the above it is immediately evident that a necessary prerequisite for a successful therapy of GISTs is the provision of accurate methods for diagnosing, staging and/or monitoring progression of such tumors, which, in turn, enable a reliable prognosis and risk assessment, and thus the selection of an appropriate therapy.
One diagnostic approach relies on immunohistochemistry, in particular on the staining of cKIT by means of specific antibodies. However, about 5-10% of the GISTs are cKIT negative. Hence, cKIT staining does not result in the reliable detection of all GISTS; additional and/or alternative methods are required
Various imaging methods are used for staging or monitoring GIST progression including positron emission-tomography (PET), computed tomography (CT), magnetic resonance tomography, and combinations thereof such as PET-CT. The most sensitive imaging technique currently available is 2-deoxy-2-(18F)fluoro-D-glucose positron emission-tomography (FDG-PET). However, the specificity and sensitivity of this method is limited so that, for example, small tumors or residual tumor activity after onset of therapy may be missed (Gambhir, S. S. et al. (2001) J. Nucl. Med. 42, 1S-93S; Antoch, G. et al. (2004) J. Nucl. Med. 45, 357-365). Furthermore, even in cases with complete response to a given therapy, lesions in most cases still contain viable tumor (Bauer, S. et al. (2005) Int. J. Cancer 117, 316-25). Thus, it is currently not possible to measure residual disease in PET-CT responders, and the trigger to change treatment is clinical or PET/CT-morphologic progression. In addition, FDG-PET (as well as other imaging methods) requires sophisticated analytical instrumentation, which is expensive both in terms of initial cost and maintenance, as well as trained personnel. This makes such systems unsuitable for routine medical practices, “bedside” testing, or in remote locations.
Accordingly, there still remains a need for improved methods and compositions that enable the rapid, reliable and cost-saving diagnosis, staging, and monitoring of gastrointestinal stromal tumors or a predisposition to develop such condition.
Thus, it is an object of the present invention to provide such methods and compositions for the diagnosis and monitoring of GISTs.